Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma

Abstract

KeywordsMonoclonal gammopathy of undetermined significance, smoldering multiple myeloma, multiple myeloma, diagnosis, management, treatment S U M M A RYMonoclonal gammopathy of undetermined significance (MGUS) is one of the most common premalignant disorders. IgG and IgA MGUS are precursor conditions of multiple myeloma (MM), whereas light-chain MGUS is a precursor condition of light-chain MM. Smoldering MM (SMM) is a precursor condition with higher tumor burden and higher risk of progression to symptomatic MM compared to MGUS. Assessment of the risk of progression of patients with asymptomatic monoclonal gammopathies is based on various factors including clonal burden, as well as biological characteristics, such as cytogenetic abnormalities and light-chain production. Several models have been constructed that are useful in daily practice for predicting risk of progression of MGUS or SMM. Importantly, the plasma cell clone may occasionally be responsible for severe organ damage through the production of a M-protein which deposits in tissues or has autoantibody activity. These disorders are rare and often require therapy directed at eradication of the underlying clone. Importantly, recent studies have shown that asymptomatic patients with a bone marrow plasma cell percentage ≥60%, free light-chain ratio ≥100, or >1 focal lesion on MRI (myeloma-defining events) have a 80% risk of developing symptomatic MM within 2 years. These patients are now considered to have MM requiring therapy, similar to patients with symptomatic disease. In this review, we provide an overview of the new diagnostic criteria of the monoclonal gammopathies and discuss risk of progression to active MM. We also provide recommendations for the management of patients with MGUS and SMM including risk-adapted follow-up.

From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells

“…A number of clinical risk factors are recognized that allow stratification of the risk of MGUS-to-MM progression. These parameters do not provide an account for underlying causes of malignant progression, but have proven useful for predicting risk of progression in individual patients (53). Important and easy to determine parameters are based on the size of the MGUS clone: both the percentage of BM PC and the baseline level and rate of increased serum M-protein level predict progression to MM (54,55).…”

“…Important and easy to determine parameters are based on the size of the MGUS clone: both the percentage of BM PC and the baseline level and rate of increased serum M-protein level predict progression to MM (54,55). Further risk factors include the heavy-chain isotypewhereby the risk of progression is most prevalent for IgD and greater for IgA/IgM MGUS than for IgG MGUS-serum free lightchain (FLC) ratio, detection of focal lesions by MRI, and Bence Jones proteinuria (53). Combining these parameters has led to the development of models predicting progression of MGUS to MM.…”

Recent advances in cytogenetic characterization of multiple myeloma

“…Some abnormalities transform normal plasma cells to MGUS, while some minor clones occur later to be a reservoir for relapse. 1,2,[4][5][6] Conventional cytogenetic studies in MM can provide the advantage of whole genome analysis with one experiment.…”

The therapeutic potential of cell cycle targeting in multiple myeloma

“…Symptomatic MM is defined by the presence of malignant plasma cells in the bone marrow (> 10% of all BM mononuclear cells) or biopsy proven plasmacytoma and one or more myeloma defining events. These myeloma defining events include evidence of end organ damage (including hypercalcemia, renal failure, anemia and bone lesions (CRAB symptoms)) or any of the following biomarkers of malignancy: clonal BM plasma cell percentage of 60% or more, involved/uninvolved serum free light chain ratio of 100 or more and more than 1 focal lesion on MRI studies [ 1 , 3 – 5 ].…”